生物活性

GDC-0994 is highly selective for ERK1 and ERK2, with biochemical potency of 1.1 nM and 0.3 nM, respectively.

The inhibition of GDC-0994[1]

^aEnzyme potency against ERK1 ; ^cInhibition of ERK dependent p90RSK serine 380 phosphorylation in PMA-stimulated HepG2 cells.

Kinase Selectivity of GDC-0994[1]

体外研究

体内研究

激酶实验

细胞实验

动物实验

In vivo PK/PD analysis[1]

HCT116 tumors were established in nude mice to a tumor volume of 400−600 mm3. Mice were treated with a single oral dose of GDC-0994 at 15, 30, or 100 mg/kg versus vehicle control alone (40% PEG400/60% (10% HPβCD)) followed by tumor and plasma collection at 2, 8, 16, and 24 h postdose. Tumor levels of phosphorylated p90RSK (pRSK) relative total p90RSK (tRSK) were measured by quantitative Western blot and were normalized to vehicle control at 2 h postdose (set to 100%). Plasma and tumor concentrations were measured by LC−MS.

Tumor growth inhibition (TGI) study

GDC-0994 was administered once daily (q.d.) orally for 21 days in nude mice bearing HCT116 human colorectal cancer subcutaneously implanted xenograft tumors.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] 1. Blake JF, Burkard M, Chan J, et al. Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-y l)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. J Med Chem. 2016;59(12):5650-5660.

体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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